There are 30,000 cases of ALS at any given time in the United States. Presently there is no cure for ALS and few treatment options. 90 percent of cases have unknown etiology, but 10 percent have a clear genetic origin. Studying the genetic cases has allowed great insight into the disease, which is applicable to both sporadic and familial cases. Continued work with animal models based on ALS-linked gene mutations and in vitro models of sporadic ALS will continue to increase knowledge of the disorder. Although ALS is characterized by the degeneration of upper and lower motor neurons there is concomitant dysfunction of glial cells. In particular, protein levels of the glial glutamate transporter EAAT2 decreases in patients and animal models of ALS. EAAT2 is cleaved by caspase 3 creating a truncated form of EAAT2 and a C-terminal fragment (CTE). A SUMOylated version of CTE (CTE-SUMO1) accumulates within the spinal cord of the SOD1-G93A mouse model of ALS. The mechanisms of CTE-SUMO1 creation must be analyzed in vitro and in vivo in order to potentially discover the mechanisms of toxicity. There are two distinct pathways that must be co-activated to create CTE- SUMO1; activation of capase-3 leading to EAAT2 cleavage and the SUMOylation of EAAT2/CTE. The proposed studies will examine the dynamics of both reactions within the parameters of ALS. In addition examination of the possible toxic effects that CTE-SUMO1 expression within astrocytes may have on neighboring motor neurons will expose another possible area of ALS pathogenesis. Previous work in a co-culture model has indicated that CTE-SUMO1 accumulation within astrocyte nuclei is toxic to neighboring motor neurons. This question will be further examined in vivo using a novel transgenic mouse model.